Ocular pharmacology and toxicology

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Ocular pharmacology and toxicology

• Hatem Kalantan, MD
• Assistant Professor
• Ophthalmology Dept.
• College of Medicine
• King Saud University

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General pharmacological principles
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Pharmacodynamics

• It is the biological and therapeutic effect of
  the drug (mechanism of action)
• Most drugs act by binding to regulatory
  macromolecules, usually neurotransmitters or
  hormone receptors or enzymes
• If the drug is working at the receptor level, it
  can be agonist or antagonist
• If the drug is working at the enzyme level, it
  can be activator or inhibitor

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Pharmacokinetics

• It is the absorption, distribution, metabolism,
  and excretion of the drug
• A drug can be delivered to ocular tissue as
• Locally
• Eye drop
• Ointment
• Periocular injection
• Intraocular injection
• Systemically
• Orally
• IV

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Factors influencing local drug penetration into
ocular tissue

• Drug concentration and solubility the higher the
  concentration the better the penetration e.g
  pilocarpine 1-4 but limited by reflex tearing
• Viscosity addition of methylcellulose and
  polyvinyl alcohol increases drug penetration by
  increasing the contact time with the cornea and
  altering corneal epithelium
• Lipid solubility because of the lipid rich
  environment of the epithelial cell membranes, the
  higher lipid solubility the more the penetration

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Factors influencing local drug penetration into
ocular tissue

• Surfactants the preservatives used in ocular
  preparations alter cell membrane in the cornea
  and increase drug permeability e.g. benzylkonium
  and thiomersal
• pH the normal tear pH is 7.4 and if the drug pH
  is much different, this will cause reflex tearing
• Drug tonicity when an alkaloid drug is put in
  relatively alkaloid medium, the proportion of the
  uncharged form will increase, thus more
  penetration

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Eye drops

• Eye drops- most common
• one drop 50 µl
• volume of conjunctival cul-de-sac 7-10 µl
• measures to increase drop absorption
• -wait 5-10 minutes between drops
• -compress lacrimal sac
• -keep lids closed for 5 minutes after
  instillation

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Ointments

• Increase the contact time of ocular medication to
  ocular surface thus better effect
• It has the disadvantage of vision blurring
• The drug has to be high lipid soluble with some
  water solubility to have the maximum effect as
  ointment

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Peri-ocular injections

• They reach behind iris-lens diaphragm better than
  topical application
• E.g. subconjunctival, subtenon, peribulbar, or
  retrobulbar
• This route bypass the conjunctival and corneal
  epithelium which is good for drugs with low lipid
  solubility (e.g. penicillins)
• Also steroid and local anesthetics can be applied
  this way

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Intraocular injections

• Intracameral or intravitreal
• E.g.
• Intracameral acetylcholine (miochol) during
  cataract surgery
• Intravitreal antibiotics in cases of
  endophthalmitis
• Intravitreal steroid in macular edema
• Intravitreal Anti-VEGF for DR

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Sustained-release devices

• These are devices that deliver an adequate supply
  of medication at a steady-state level
• E.g.
• Ocusert delivering pilocarpine
• Timoptic XE delivering timolol
• Ganciclovir sustained-release intraocular device
• Collagen shields

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Systemic drugs

• Oral or IV
• Factor influencing systemic drug penetration into
  ocular tissue
• lipid solubility of the drug more penetration
  with high lipid solubility
• Protein binding more effect with low protein
  binding
• Eye inflammation more penetration with ocular
  inflammation

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Ocular pharmacotherapeutics
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Cholinergic agonists

• Directly acting agonists
• E.g. pilocarpine, acetylcholine (miochol),
  carbachol (miostat)
• Uses miosis, glaucoma
• Mechanisms
• Miosis by contraction of the iris sphincter
  muscle
• increases aqueous outflow through the trabecular
  meshwork by longitudinal ciliary muscle
  contraction
• Accommodation by circular ciliary muscle
  contraction
• Side effects
• Local diminished vision (myopia), headache,
  cataract, miotic cysts, and rarely retinal
  detachment
• systemic side effects lacrimation, salivation,
  perspiration, bronchial spasm, urinary urgency,
  nausea, vomiting, and diarrhea

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Cholinergic agonists

• Indirectly acting (anti-cholinesterases)
• More potent with longer duration of action
• Reversible inhibitors
• e.g. physostigmine
• used in glaucoma and lice infestation of lashes
• can cause CNS side effects

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Cholinergic agonists

• Indirectly acting (anticholinesterases)
• Irreversible
• e.g. phospholine iodide
• Uses in accommodative esotropia
• side effects iris cyst and anterior subcapsular
  cataract
• C/I in angle closure glaucoma, asthma,
  Parkinsonism
• causes apnea if used with succinylcholine or
  procaine

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Cholinergic antagonists

• E.g. tropicamide, cyclopentolate, homatropine,
  scopolamine, atropine
• Cause mydriasis (by paralyzing the sphincter
  muscle) with cycloplegia (by paralyzing the
  ciliary muscle)
• Uses fundoscopy, cycloplegic refraction,
  anterior uveitis
• Side effects
• local allergic reaction, blurred vision
• Systemic nausea, vomiting, pallor, vasomotor
  collapse, constipation, urinary retention, and
  confusion
• specially in children they might cause flushing,
  fever, tachycardia, or delerium
• Treatment by DC or physostigmine

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Adrenergic agonists

• Non-selective agonists (a1, a2, ß1, ß2)
• E.g. epinephrine, depevefrin (pro-drug of
  epinephrine)
• Uses glaucoma
• Side effects headache, arrhythmia, increased
  blood pressure, conjunctival adrenochrome,
  cystoid macular edema in aphakic eyes
• C/I in closed angle glaucoma

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Adrenergic agonists

• Alpha-1 agonists
• E.g. phenylepherine
• Uses mydriasis (without cycloplegia),
  decongestant
• Adverse effect
• Can cause significant increase in blood pressure
  specially in infant and susceptible adults
• Rebound congestion
• precipitation of acute angle-closure glaucoma in
  patients with narrow angles

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Adrenergic agonists

• Alpha-2 agonists
• E.g. brimonidine, apraclonidine
• Uses glaucoma treatment, prophylaxis against IOP
  spiking after glaucoma laser procedures
• Mechanism decrease aqueous production, and
  increase uveoscleral outflow
• Side effects
• local allergic reaction, mydriasis, lid
  retraction, conjunctival blanching
• systemic oral dryness, headache, fatigue,
  drowsiness, orthostatic hypotension, vasovagal
  attacks
• Contraindications infants, MAO inhibitors users

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Alpha adrenergic antagonists

• E.g. thymoxamine, dapiprazole
• Uses to reverse pupil dilation produced by
  phenylepherine
• Not widely used

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Beta-adrenergic blockers

• E.g.
• non-selective timolol, levobunolol,
  metipranolol, carteolol
• selective betaxolol (beta 1 cardioselective)
• Uses glaucoma
• Mechanism reduce the formation of aqueous humor
  by the ciliary body
• Side effects bronchospasm (less with betaxolol),
  cardiac impairment

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Carbonic anhydrase inhibitors

• E.g. acetazolamide, methazolamide,
  dichlorphenamide, dorzolamide, brinzolamide.
• Uses glaucoma, cystoid macular edema,
  pseudotumour cerebri
• Mechanism aqueous suppression
• Side effects myopia, parasthesia, anorexia, GI
  upset, headache, altered taste and smell, Na and
  K depletion, metabolic acidosis, renal stone,
  bone marrow suppression aplastic anemia
• Contraindication sulpha allergy, digitalis
  users, pregnancy

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Osmotic agents

• Dehydrate vitreous body which reduce IOP
  significantly
• E.G.
• glycerol 50 syrup (cause nausea, hyperglycemia)
• Mannitol 20 IV (cause fluid overload and not
  used in heart failure)

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Prostaglandin analogues

• E.g. latanoprost, bimatoprost, travoprost,
  unoprostone
• Uses glaucoma
• Mechanism increase uveoscleral aqueous outflow
• Side effects darkening of the iris
  (heterochromia iridis), lengthening and
  thickening of eyelashes, intraocular
  inflammation, macular edema

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Corticosteroids

• Topical
• E.g. fluorometholone, remixolone, prednisolone,
  dexamethasone, hydrocortisone
• Mechanism inhibition of arachidonic acid release
  from phospholipids by inhibiting phosphlipase A2
• Uses postoperatively, anterior uveitis, severe
  allergic conjunctivitis, vernal
  keratoconjunctivitis, prevention and suppression
  of corneal graft rejection, episcleritis,
  scleritis
• Side effects susceptibility to infections,
  glaucoma, cataract, ptosis, mydriasis, scleral
  melting, skin atrophy

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Corticosteroids

• Systemic
• E.g. prednisolone, cortisone
• Uses posterior uveitis, optic neuritis, temporal
  arteritis with anterior ischemic optic neuropathy
• Side effects
• Local posterior subcapsular cataract, glaucoma,
  central serous retinopathy
• Systemic suppression of pituitary-adrenal axis,
  hyperglycemia, osteoporosis, peptic ulcer,
  psychosis

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NSAID

• E.g. ketorolac, diclofenac, flurbiprofen
• Mechanism inactivation of cyclo-oxygenase
• Uses postoperatively, mild allergic
  conjunctivitis, episcleritis, mild uveitis,
  cystoid macular edema, preoperatively to prevent
  miosis during surgery
• Side effects stinging

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Anti-allergics

• Avoidance of allergens, cold compress,
  lubrications
• Antihistamines (e.g.pheniramine, levocabastine)
• Decongestants (e.g. naphazoline, phenylepherine,
  tetrahydrozaline)
• Mast cell stabilizers (e.g. cromolyn, lodoxamide,
  pemirolast, nedocromil, olopatadine)
• NSAID (e.g. ketorolac)
• Steroids (e.g. fluorometholone, remixolone,
  prednisolone)
• Drug combinations

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Antibiotics

• Penicillins
• Cephalosporins
• Sulfonamides
• Tetracyclines
• Chloramphenicol
• Aminoglycosides
• Fluoroquinolones
• Vancomycin
• macrolides

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Antibiotics

• Used topically in prophylaxis (pre and
  postoperatively) and treatment of ocular
  bacterial infections.
• Used orally for the treatment of preseptal
  cellulitis
• e.g. amoxycillin with clavulonate, cefaclor
• Used intravenously for the treatment of orbital
  cellulitis
• e.g. gentamicin, cephalosporin, vancomycin,
  flagyl
• Can be injected intravitrally for the treatment
  of endophthalmitis

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Antibiotics

• Trachoma can be treated by topical and systemic
  tetracycline or erythromycin, or systemic
  azithromycin.
• Bacterial keratitis (bacterial corneal ulcers)
  can be treated by topical fortified penicillins,
  cephalosporins, aminoglycosides, vancomycin, or
  fluoroquinolones.
• Bacterial conjunctivitis is usually self limited
  but topical erythromycin, aminoglycosides,
  fluoroquinolones, or chloramphenicol can be used

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Antifungals

• Uses fungal keratitis, fungal endophthalmitis
• Polyenes
• damage cell membrane of susceptible fungi
• e.g. amphotericin B, natamycin
• side effect nephrotoxicity
• Imidazoles
• increase fungal cell membrane permeability
• e.g. miconazole, ketoconazole
• Flucytocine
• act by inhibiting DNA synthesis

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Antivirals

• Acyclovir
• interact with viral thymidine kinase (selective)
• used in herpetic keratitis
• Trifluridine
• more corneal penetration
• can treat herpetic iritis
• Ganciclovir
• used intravenously for CMV retinitis

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Ocular diagnostic drugs

• Fluorescein dye
• Available as drops or strips
• Uses stain corneal abrasions, applanation
  tonometry, detecting wound leak, NLD obstruction,
  fluorescein angiography
• Caution
• stains soft contact lens
• Fluorescein drops can be contaminated by
  Pseudomonas sp.

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Ocular diagnostic drugs

• Rose bengal stain
• Stains devitalized epithelium
• Uses severe dry eye, herpetic keratitis

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Local anesthetics

• topical
• E.g. propacaine, tetracaine
• Uses applanation tonometry, goniscopy, removal
  of corneal foreign bodies, removal of sutures,
  examination of patients who cannot open eyes
  because of pain
• Adverse effects toxic to corneal epithelium,
  allergic reaction rarely

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Local anesthetics

• Orbital infiltration
• peribulbar or retrobulbar
• cause anesthesia and akinesia for intraocular
  surgery
• e.g. lidocaine, bupivacaine

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Other ocular preparations

• Lubricants
• drops or ointments
• Polyvinyl alcohol, cellulose, methylcellulose
• Preserved or preservative free

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Ocular toxicology
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Complications of topical administration

• Mechanical injury from the bottle e.g. corneal
  abrasion
• Pigmentation epinephrine- adrenochrome
• Ocular damage e.g. topical anesthetics,
  benzylkonium
• Hypersensitivity e.g. atropine, neomycin,
  gentamicin
• Systemic effect topical phenylephrine can
  increase BP

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Amiodarone

• A cardiac arrhythmia drug
• Causes optic neuropathy (mild decreased vision,
  visual field defects, bilateral optic disc
  swelling)
• Also causes corneal vortex keratopathy (corneal
  verticillata) which is whorl-shaped pigmented
  deposits in the corneal epithelium

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Digitalis

• A cardiac failure drug
• Causes chromatopsia (objects appear yellow) with
  overdose

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Chloroquines

• E.g. chloroquine, hydroxychloroquine
• Used in malaria, rheumatoid arthritis, SLE
• Cause vortex keratopathy (corneal verticillata)
  which is usually asymptomatic but can present
  with glare and photophobia
• Also cause retinopathy (bulls eye maculopathy)

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Chorpromazine

• A psychiatric drug
• Causes corneal punctate epithelial opacities,
  lens surface opacities
• Rarely symptomatic
• Reversible with drug discontinuation

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Thioridazine

• A psychiatric drug
• Causes a pigmentary retinopathy after high dosage

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Diphenylhydantoin

• An epilepsy drug
• Causes dosage-related cerebellar-vestibular
  effects
• Horizontal nystagmus in lateral gaze
• Diplopia, ophthalmoplegia
• Vertigo, ataxia
• Reversible with the discontinuation of the drug

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Topiramate

• A drug for epilepsy
• Causes acute angle-closure glaucoma (acute eye
  pain, redness, blurred vision, haloes).
• Treatment of this type of acute angle-closure
  glaucoma is by cycloplegia and topical steroids
  (rather than iridectomy) with the discontinuation
  of the drug

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Ethambutol

• An anti-TB drug
• Causes a dose-related optic neuropathy
• Usually reversible but occasionally permanent
  visual damage might occur

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Agents that Can Cause Toxic Optic Neuropathy

• Methanol
• Ethylene glycol (antifreeze)
• Chloramphenicol
• Isoniazid
• Ethambutol
• Digitalis
• Chloroquine
• Streptomycin
• Amiodarone
• Quinine
• Vincristine and methotrexate (chemotherapy
  medicines)
• Sulfonamides
• Melatonin with Zoloft (sertraline, Pfizer) in a

• high-protein diet
• Carbon monoxide
• Lead
• Mercury
• Thallium (alopecia, skin rash, severe vision
  loss)
• Malnutrition with vitamin B-1 deficiency
• Pernicious anemia (vitamin B-12 malabsorption
• phenomenon)
• Radiation (unshielded exposure to gt3,000 rads).

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HMG-CoA reductase inhibitors (statins)

• Cholesterol lowering agents
• E.g. pravastatin, lovastatin, simvastatin,
  fluvastatin, atorvastatin, rosuvastatin
• Can cause cataract in high dosages specially if
  used with erythromycin

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Other agents

• methanol optic atrophy and blindness
• Contraceptive pills pseudotumor cerebri
  (papilledema), and dryness (CL intolerance)
• Chloramphenicol and streptomycin optic atrophy
• Hypervitaminosis A yellow skin and conjunctiva,
  pseudotumor cerebri (papilledema), retinal
  hemorrhage.
• Hypovitaminosis A night blindness (nyctalopia),
  keratomalacia.

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Thank you
Any question?